Perivascular spaces in the brain: anatomy, physiology and pathology

Abstract

Perivascular spaces include a variety of passageways around arterioles, capillaries and venules in the brain, along which a range of substances can move. Although perivascular spaces were first identified over 150 years ago, they have come to prominence recently owing to advances in knowledge of their roles in clearance of interstitial fluid and waste from the brain, particularly during sleep, and in the pathogenesis of small vessel disease, Alzheimer disease and other neurodegenerative and inflammatory disorders. Experimental advances have facilitated in vivo studies of perivascular space function in intact rodent models during wakefulness and sleep, and MRI in humans has enabled perivascular space morphology to be related to cognitive function, vascular risk factors, vascular and neurodegenerative brain lesions, sleep patterns and cerebral haemodynamics. Many questions about perivascular spaces remain, but what is now clear is that normal perivascular space function is important for maintaining brain health. Here, we review perivascular space anatomy, physiology and pathology, particularly as seen with MRI in humans, and consider translation from models to humans to highlight knowns, unknowns, controversies and clinical relevance.

Key points

  • Visible perivascular spaces on MRI increase in number with age, vascular risk factors (particularly hypertension) and other features of small vessel disease, indicating that they are clinically relevant.

  • Perivascular space dilation on MRI is a marker of perivascular space dysfunction and, by implication from preclinical studies, impairment of normal brain fluid and waste clearance and microvascular dysfunction.

  • Perivascular spaces can be quantified using visual scores of perivascular spaces in standard brain regions and now also with computational measures of perivascular space count, volume, length, width, sphericity and orientation.

  • Experimental models show that perivascular spaces are important conduits for uptake of cerebrospinal fluid to flush interstitial fluid and clear metabolic waste; these processes seem to increase during sleep.

  • The relative importance of different drainage routes from perivascular spaces in humans remains to be determined.

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Fig. 1: Perivascular spaces visualized with MRI in humans.
Fig. 2: High-field and conventional MRI of perivascular spaces in humans in vivo.
Fig. 3: Perivascular spaces and small vessel disease.
Fig. 4: Relationship of perivascular spaces to arterioles and venules in humans.
Fig. 5: Uptake of cerebrospinal fluid tracer into perivascular spaces in the whole rat brain visualized by optimal mass transport.
Fig. 6: Anatomy of perivascular spaces around basal and cortical perforating arterioles.
Fig. 7: Uptake of cerebrospinal fluid into perivascular spaces in rodents and humans.
Fig. 8: Movement of fluid in perivascular spaces.

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Acknowledgements

The authors acknowledge the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease (grant reference 16 CVD 05). F.N.D. is supported by a Garfield Weston Stroke Association Fellowship and an NHS Research Fellowship from the Scottish Government.

Review criteria

We searched the literature from the mid-1800s to the present for papers on ‘perivascular spaces’, ‘glymphatics’, ‘Virchow–Robin spaces’, ‘small vessel disease’, ‘cerebrospinal fluid’, ‘cerebral blood flow’, ‘white matter hyperintensities’, ‘lacunes’, ‘microbleeds’, ‘siderosis’, ‘stroke’, ‘dementia’, ‘cognition’, ‘magnetic resonance imaging’, ‘2-photon imaging’, ‘electron microscopy’ and ‘immunohistochemistry’. Where available, we used recent systematic reviews and updated their contents. We looked for additional relevant papers in reference lists of review articles and research papers. Our approach was not systematic owing to the breadth of the field, but we aimed to capture key papers in the field. We discussed and debated at length the historical and recent findings in our Leducq research network.

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J.M.W. searched the literature and drafted the paper. H.B., M.N., B.V.Z., H.M., F.N.D., J.R., A.T., R.L.R., D.B., M.S. and A.M. provided additional text, figures or references. H.B., M.N., B.V.Z., H.M., H.L., A.J., S.E.B., F.N.B., R.B., J.R., B.J.M., A.T., L.B., R.L.R., D.B., M.S., A.M., S.C. and K.J.S. all commented on and edited the text. All authors approved the submitted version.

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Correspondence to Joanna M. Wardlaw.

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The authors declare support from academic grants but have no other competing interests. The authors’ institutions receive grant support related to the work described in the paper from the Fondation Leducq (16 CVD 05), the USA National Institutes of Health, the UK Medical Research Council, Stroke Association, Alzheimer’s Society, and Row Fogo Charitable Trust.

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Nature Reviews Neurology thanks R. Carare, A. Charidimou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Fondation Leducq Transatlantic Network of Excellence on the Role of the Perivascular Space in Cerebral Small Vessel Disease: www.small-vessel-disease.org

Harmonising Brain Imaging Methods for Vascular Contributions to Neurodegeneration (HARNESS): https://harness-neuroimaging.org/

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Glossary

Perivascular spaces

Spaces or potential spaces around arterioles, capillaries and venules in the brain, along which fluid or particles can pass; not restricted to Virchow–Robin spaces.

Virchow–Robin spaces

Macroscopic spaces, originally identified in postmortem brain specimens, surrounding the perforating vessels in the basal ganglia and hemispheric white matter; thought to correspond to the perivascular spaces that are visible on brain MRI.

Optimal mass transport

(OMT). A method of analysing the passage of a fluid (for example, contrast agent) though a volume (for example, the intracranial cavity).

Lacunes

Small holes in the deep grey or white matter, often the sequelae of a small deep lacunar infarct but commonly found in persons with no prior symptoms; increases with age, associated with cognitive decline, part of the spectrum of small vessel disease.

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Wardlaw, J.M., Benveniste, H., Nedergaard, M. et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol 16, 137–153 (2020). https://doi.org/10.1038/s41582-020-0312-z

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